E46K Mutation of α-Synuclein Preorganizes the Intramolecular Interactions Crucial for Aggregation

Aggregation of & alpha;-synuclein is central to the pathogenesisof Parkinson's disease. The most toxic familial mutation E46Kaccelerates the aggregation process by an unknown mechanism. Herein,we provide a clue by investigating the influence of E46K on monomeric & alpha;-synuclein and its relation to aggregation with molecular dynamicssimulations. The E46K mutation suppresses & beta;-sheet structuresin the N-terminus while promoting those at the key fibrillizationregion named NACore. Even though WT and E46K monomers share conservedintramolecular interactions with fibrils, E46K abolishes intramolecularcontacts within the N-terminus which are present in the WT monomerbut absent in fibrils. Network analysis identifies residues 36-53as the interaction core of the WT monomer. Upon mutation, residues36-46 are expelled to water due to aggravated electrostaticrepulsion in the (KTKK46)-K-43 segment. Instead,NACore (residues 68-78) becomes the interaction hub and connectspreceding residues 47-56 and the C-terminus. Consequently,residues 47-95 which belong to the fibril core form more compact & beta;-sheets. Overall, the interaction network of E46K is more likefibrils than WT, stabilizing the fibril-like conformations. Our workprovides mechanistic insights into the faster aggregation of the E46Kmutant. It implies a close link between monomeric conformations andfibrils, which would spur the development of therapeutic strategies.

Automated summary

Aggregation of α-synuclein is critical in Parkinson's disease, and the E46K mutation accelerates this process. Through molecular dynamics simulations, we found that E46K mutation affects the structure of monomeric α-synuclein, promoting β-sheet formation in the fibrillization region while suppressing it in the N-terminus. The mutation also led to changes in intramolecular interactions and network topology, making the E46K mutant more similar to fibrils than the wild type. These findings shed light on the mechanism behind the faster aggregation of the E46K mutant and suggest potential therapeutic strategies.